DK164061B - SOLVATE OF A CEPHALOSPORIN INTERMEDIATE PRODUCT AND PROCEDURE FOR THE PREPARATION OF SUCH SOLVAT - Google Patents

Description

in

DK 164061 B

The present invention relates to novel solvates of an intermediate for the preparation of ceftazidime, and the invention further relates to a process for producing these solvates.

5

There is a continuing need for the development of new antibiotics' due to the constant risk of developing strains of pathogenic microorganisms resistant to specific antibiotics. Because of the high costs associated with developing antibiotics, not least cephalosporin antibiotics, researchers are constantly looking for new and effective methods for producing these antibiotics.

In this regard, United States Patent Specification no.

4 258 041 synthesis of (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1) (pyridinium methyl) ceph-3-em-4-carboxylate, which is a cephalosporin antibiotic now known generically as ceftazidime.

The synthesis of ceftazidime described consists of reacting (Z) -2- (2-tert-butoxycarbonylprop-2-oxyimino) -2- (2-triphenylmethylaminothiazol-4-yl) acetyl chloride with (6R, 7R) -7-Amino-3- (1-pyridinium methyl) ceph-3-em-4-carboxylic acid in a mixture of Ν, Ν-dimethylacetamide and acetonitrile to give the ceftazidime intermediate (6R, 7R) -7 - [(Z) -2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert.-butoxycarbonylprop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl) ceph-3-em -4-carboxylate. This ceftazi-dim intermediate is then recovered from the reaction mixture as an amorphous solid which can be purified by crystallization from Ν, Ν-dimethylformamide in the form of an N, N-dimethylformamide solvate (2.5 moles DMF per mole intermediate). Thereafter, the ceftazidime intermediate may be reacted with formic acid, which reaction causes a removal of the protecting groups and leads to the formation of ceftazidime.

DK 164061 B

2

The present invention provides an improved process for preparing the ceftazidime intermediate, whereby the intermediate is directly crystallized from the reaction mixture as an N, N-dimethylacetamide-solvate. The invention thus eliminates the need for subsequent purification and leads to improved yields and reduced costs. in the production of ceftazidime.

In accordance with the invention, a compound of the general formula is 0-ΥΧΛ. , „Iwf si 1 Y Y A, \ <f \ / / • H C-C-CH I _ on 3 3 C00 20 9Hs

COO-CCH

I 3

CH

3 xDMAC. .

Wherein DMAC means N, N-dimethylacetamide and x is a number from 0.5 to 3.0, thus a useful solvate of an intermediate in the synthesis of ceftazidime.

30

As mentioned, the invention also relates to a process for the preparation of a compound of formula (I), which is characterized by the fact that, in N, N-dimethylacetamide, a ((Z) -2- (2-tert)) is reacted. -35-butoxy-carbonylprop-2-oxyimino) -2- (2-triphenylmethylamino-thiazol-4-yl) acetyl halide with an (6R, 7R) -7-amino-3- (1-pyridinium methyl) ceph-3 em-4-carboxylic acid salt.

DK 164061 B

3 suiting ethyl acetamide solvate can be isolated directly from the reaction mixture in the form of a crystalline solid. The process of the invention allows to isolate a substantially pure ceftazidime intermediate in the form of an N, N-dimethylacetamide solvate in good yields.

The term "ceftazidime intermediate" as used herein means (6R, 7R) -7 - [(Z) -2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert-butoxy-carbonylprop-2) (oxyimino-acetamido] -3- (1-pyridinium-methyl) -ceph-3-em-4-carboxylate. The process by which this ceftazidime intermediate is prepared involves a typical acylation reaction, thereby reacting a cephalosporin core (ie, a 7-amino-3-cephem derivative) with an acid halide, typically an acid chloride. The acid halide typically used in the synthesis of the ceftazidime intermediate is a (Z) -2- (2-tert-butoxy-carbonylprop-2-oxyimino) -2- (2-triphenylmethylamino-thiazol-4-yl) -eddikesyrehalogenid. Acylation is generally accomplished by reacting the acid halide 20 with about an equimolar amount of the 7-amino-3-cephem nucleus in a non-reactive solvent such as dichloromethane, acetone or a mixture of N, N-dimethylacetamide and acetonitrile. , also working in the presence of. A base such as triethylamine or pyridine. The process can be improved by using N, N-dimethylacetamide as the solvent for the reaction to obtain the ceftazidime intermediate directly from the reaction mixture by the acylation in the form of a crystalline N, N-dimethylacetamide solvate. This improved process eliminates the separate purification step during which the ceftazidime intermediate is converted to a solvate such as the N, N-dimethylformamide solvate.

By carrying out the process of the invention 35, the acid halide can be prepared, e.g. (Z) -2- (2-tert-Butoxycarbonylprop-2-oxyimino) -2- (2-triphenylmethyl-amino-thiazol-4-yl) acetyl chloride, by reacting it

DK 164061B

4 free acid with a halogenating agent such as phosphorus pentachloride in a suitable solvent such as dichloromethane or ethyl ether. Once the acid halide is formed, it is not normally isolated but instead added to a suspension of about an equimolar amount of the cephalosporin nucleus in Ν, Ν-dimethylacetamide. An appropriate base, such as triethylamine, is added to the reaction mixture to serve as a binding agent for any free acid present. The acylation reaction is typically complete within about 10 minutes. 15 and approx. 90 minutes when carried out at a temperature of approx. -20 and approx. 40 ° C. The ceftazidime intermediate thus produced is a Ν, Ν-dimethylacetamide solvate of formula (I) shown above, wherein DMAC means Ν, Ν-dimethylacetamide, and x is a number from 0.5 to 3.0 and denotes the number of moles of DMAC per mole of ceftazidime intermediate. Preferred solvates are those wherein x is from 0.5 to about 1.5, especially those where x is 1.0.

The ceftazidime intermediate in the form of a solvate can be readily isolated, if desired, by washing the reaction mixture with water and then adding a suitable anti-solvent, ie. a solvent in which intermediate. -it is essentially insoluble. Typical anti-solvents include ethers such as diethyl ether, methyl ethyl ether, glycol methyl ether or tetrahydrofuran, and esters such as ethyl acetate or methyl acetate. The preferred anti-solvent is diethyl ether or a combination of diethyl ether and ethyl acetate.

When the anti-solvent is added to the reaction mixture containing Ν, Ν-dimethylacetamide, the ceftazidime intermediate in the form of the N, N-dimethylacetamide solvate will start to precipitate over about 30 to 90 minutes if the solution is stirred at a temperature of between ca. -10 and approx. + 10 ° C. The crystalline solvate is isolated by simple filtration of the mixture, and generally it is desired to

DK 164061 B

Wash the solvate with fresh N, N-dimethylacetamide or diethyl ether. The product can be air dried at room temperature or dried in vacuo to remove any excess solvent. The product formed is a 5 Ν, Ν-dimethylacetamide solvate of ceftazidime intermediate having a purity generally above about 90%.

The ceftazidime intermediate obtainable as a solvate according to the invention can be used directly for the preparation of ceftazidime. Eg. one can dissolve the crystalline solvate in an acidic solution, e.g. 98% formic acid, to remove the protecting triphenylmethyl group from the amino group attached to the thiazolylacetamido side chain, and also to remove the protective tert-butoxy group from the oxime portion of the side chain. If desired, hydrochloric acid can be added to form the dihydrochloride salt of ceftazidime, which facilitates the production of the final product as a crystalline precipitate. The ceftazidime dihydrochloride thus obtained can be used as an antibiotic.

The invention is further illustrated by the following examples. . EXAMPLE 1 (6R, 7R) -7 - [(Z) -2- (Triphenylmethylamino-thiazol-4-yl) -2- (2-tert-butoxycarbonylpropoxyimino) acetamido] -3- (1-pyridinium methyl) ) ceph-3-em-4-carboxylate 30

To a cold (-10 ° C) stirred solution of 9.70 g (41.8 mM) phosphorus pentachloride in 150 ml of dichloromethane was added 21.72 g (38 mM) (Z) -2- (2-tert-butoxycarbonylpropyl) 2-oxyimino) -. 2- (2-triphenylmethylaminothiazol-4-yl) acetic acid. The reaction mixture was stirred for 30 minutes at -10 ° C and then diluted with a cold solution consisting of 100 ml of water containing 11.66 ml (83.6 mM) of trihydrate.

DK 164061 B

6 ethylamine. The two-phase reaction mixture was stirred vigorously for about 3 minutes, after which the organic phase was removed and added to a stirred cold (-10 ° C) suspension of 16.89 g (38.0 mM) (6R, 7R). ) -7-Amino-3-5 (1-pyridinium methyl) ceph-3-em-4-carboxylic acid dihydrochloride in 195 ml of Ν, Ν-dimethylacetamide containing 26.5 ml (190 mM) of triethylamine. The reaction mixture was stirred at a temperature of between 0 and -5 ° C for 30 minutes and then diluted by adding 300 ml of 10 water in one portion. The aqueous reaction mixture was stirred for 10 minutes, then the organic phase was separated and further diluted by adding 150 ml of fresh Ν, Ν-dimethylacetamide and 300 ml of diethyl ether.

The organic solution was stirred at 0-5 ° C for 1 hour, after which the crystalline precipitate formed was easily collected by filtration, washed with fresh Ν, Ν-dimethylacetamide and then with fresh diethyl ether and dried at ambient temperature in vacuum for 16 hours. . There was thus obtained 20.96 g (65.2%) of (6R, 7R) -7 - [(Z) -2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert.p. butoxycarbonyl-prop-2-oxyimino) acetamido] -3- (1-pyridinium methyl) ceph-3-em-4-carboxylate-N, N-dimethylacetamide-solvate (1-mole Ν, Ν-dimethylacetamide) with a melting point at 150 ° C (decomposition). The purity was. -95.56% as determined by high pressure liquid chromatography.

EXAMPLE 2

The process described in Example 1 was repeated as follows:

To a cold (-15 ° C) stirred solution of 7.73 g of phosphorus pentachloride in 120 ml of dichloromethane was added 17.32 g of (Z) -2- (2-tert-butoxycarbonylprop-2-oxyimino) -2- ( 2-triphenylme-thylaminothiazol-4-yl) -acetic acid. The reaction mixture was stirred for 30 minutes while maintaining the temperature between ca. -10 and approx. -15 ° C. Then, the reaction mixture was diluted by the addition of 80 ml of water containing 7 10.5 ml of triethylamine. After stirring the reaction mixture for 3 minutes, the organic phase was separated and the aqueous phase was poured. The organic phase was then added dropwise over 10 minutes to a 5 cold (-10 ° C) stirred suspension of 11.3 g (6R, 7R) -7-amino-3- (1-pyridinium methyl) -ceph -3-em-4-carboxylic acid dihydrochloride in 88 ml of N, N-dimethylacetamide containing 17.5 ml of triethylamine. The reaction mixture was stirred for 30 minutes at a temperature of between ca. -5 and approx. 0 ° C, after which the mixture was allowed to warm to about +5 ° C, at which temperature it was diluted by the addition of 200 ml of water. After stirring the aqueous mixture for 2 minutes, the organic phase was separated and the aqueous phase was poured. The organic phase 15 was further diluted with 200 ml of ethyl acetate and 100 ml of diethyl ether and the mixture was stirred vigorously at about 20 to about 25 ° C. Then, the mixture was seeded with the ceftazidime intermediate in the form of the N, N-dimethylacetamide solvate to trigger crystallization. After stirring the mixture for 30 minutes at 20-25 ° C, the temperature was lowered to 0 ° C and stirring continued for about 2 hours. The mixture was filtered and the filter cake was washed with a mixture of 10 ml of N, N-dimethylacetamide. and 10 ml of diethyl ether and then with 40 ml of diethyl ether, and after drying at 35 ° C under vacuum for about 16 hours, a yield of the ceftazidime intermediate as N, N-dimethylacetamide-solvate (1.5 mole of N, N-dimethylacetamide) was obtained. ) of about 78%.

EXAMPLE 3

Ceftazidime dihydrochloride

To a 250 ml three neck round bottom flask which had been pre-purified with nitrogen was added 62.2 ml (75.9 g) formic acid which was cooled to about 15 ° C. To the stirred cooled formic acid was added 32.0 g (37.9 mM)

DK 164061 B

The ceftazidime intermediate of Example 1 or 2. The solution was stirred for 30 minutes, then 30 ml (15.8 g) of hydrochloric acid was added while maintaining the temperature below 20 ° C. The mixture was stirred for about 3 hours and the resulting triphenylmethanol was filtered off and washed with formic acid and water. The filtrate was cooled and added to about 850 ml of acetone and the cooled slurry stirred for about 2 hours. The product was filtered off and washed with acetone to give the title product in a yield of about 62%.

NMR (DMSO-d 6); δ 1.58 (s, 2 -CH 3); δ 5.33 (d, J = 5 Hz, 6-H); δ 6.01 (dd, J = 9.5 Hz; 7-H); δ 7.00 (s, aminothiazole); δ 8.30; 8.75 (t, J = 6 Hz); δ 8.75 (t, J = 6 Hz); δ 9.23 (d, 15 J = 6 Hz, pyridinium protons); δ 9.72 (d, J = 9, acetamido proton).

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Claims (7)

A solvate of a cephalosporin intermediate, characterized in that it has the general formula Patent claim: 10 (cWxi 'in V · V => N— \ AY A. (I) a QI - is 1 * ”Y V'O H Ct-CH T _ s 3 C00 CH 13 6oo-cch3 CH 3 XDMAC 20 wherein DMAC is N, N-dimethylacetamide and x is a number from 0.5 to 3.0. . - Solvate according to claim 1, characterized in that x is 0.5. Solvate according to claim 1, characterized in that x is 1.0. 30 Solvate according to claim 1, characterized in that x is 1.5. . Solvate according to claim 1, characterized in that x 35 is 2.0. DK 164061 B Solvate according to claim 1, characterized in that x is 2.5. A process for preparing the solvate of formula 5 (I) according to any one of claims 1-6 by reaction in N, N-dimethylacetamide of a ((Z) -2- (2-tert-butoxycarbonyl-prop-2-oxyimino) ) -2- (2-Triphenylmethylamino-thiazol-4-yl) acethyl halide with a (6R, 7R) -7-amino-3 (1-pyridinimethyl) ceph-3-em-4-carboxylate acid salt, known as The character is that after the reaction, the reaction mixture is washed with water and an anti-solvent is added to precipitate the solvate. 15 20 25 30 35